Normal human somatic cells have finite replicative life spans when cultured in vitro. This phenomenon of "clonal senescence" may be regarded as a useful model for the study of certain aspects of cell aging. The proposed experiments attempt to elucidate the mechanism(s) of such clonal senescence by a variety of somatic cell genetic experiments involving heterokaryons, synkaryons and cybrids between postreplicative "old" cells and both euploid and heteroploid actively replicating cells and also between Gl(G0) cells and various cell types in the DNA synthetic phase of the cell cycle. Attempts to identify specific proteins involved in the regulation of cell proliferation will be made in complementation studies with conditional lethal cell cycle mutants, in vitro analysis of the activity of cell free extracts, and by microinjection of cell extracts. The general hypothesis being tested is that clonal senescence is a genetically regulated phenomenon.